Circulating LDL that enters the blood vessel wall is the main source of cholesterol that accumulates within vessel wall atherosclerotic plaques, the cause of most heart attacks and strokes. Much of the deposited cholesterol accumulates within plaque macrophages converting these macrophages into cholesterol-rich foamy looking cells. Plaque macrophages are derived from circulating monocytes that enter the vessel wall and then differentiate into macrophages. Cholesterol accumulation in macrophages not only contributes to cholesterol retention within the vessel wall, but also alters macrophage biology. Cholesterol-loaded macrophages secrete plaque disrupting matrix metalloproteinase enzymes and produce tissue factor that promotes thrombosis when plaques rupture. Thus, how macrophages accumulate cholesterol and become foam cells has been the subject of intense investigation. It is generally believed that only LDL modified by oxidation, but not native (i.e., unmodified) LDL, can cause cholesterol accumulation in macrophages. However, most LDL within atherosclerotic plaques is not oxidized, and oxidized LDL is a poor inducer of macrophage cholesterol accumulation. In the present research project, we have investigated how modification of macrophages rather than modification of LDL affects macrophage metabolism of native LDL. We have learned that macrophage cholesterol accumulation can occur with native LDL when macrophages are activated either through protein kinase C signaling pathways or by differentiation of monocytes into activated macrophages with specific cytokines and growth factors. Both pathways to activated human monocyte-derived macrophages stimulate macrophage uptake and degradation of native LDL. LDL uptake does not depend on macrophage oxidation of LDL or macrophage binding of LDL. Rather, the activated macrophages show greatly stimulated macropinocytosis, a process by which macrophages and some other cell types take up large amounts of fluid. The activated macrophages take up LDL as part of the fluid that they ingest during macropinocytosis. This produces cholesterol accumulation in macrophages to levels characteristic of macrophage foam cells in atherosclerotic plaques. This novel mechanism of macrophage cholesterol accumulation shows that modification of LDL is not necessary for foam cell formation to occur. In addition, the findings direct attention to macrophage macropinocytosis as a relevant pathway to target for modulating macrophage cholesterol accumulation in atherosclerosis.